Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents

ABSTRACT

The invention relates to the use of derivatives of F-type prostaglandins as ocular hypotensives. The compounds used in accordance with the invention are represented by the following formula I: ##STR1## wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; hatched segments indicate a configuration; the solid triangle is used to indicate β configuration; dashed bonds represent a double bond, or a single bond; R is a substituted heteroaryl radical having at least two pendant substituents selected from the group consisting of C 1  to C 6  alkyl; halogen; trifluoromethyl; COR 1  ; COCF 3  ; SO 2  NR 1  ; NO 2  and CN or at least one cyano group; R 1  is hydrogen or a lower alkyl radical having up to six carbon atoms, X is selected from the group consisting of --OR 1  and --N(R 1 ) 2  ; Y is ═O or represents 2 hydrogen radicals and the 9, 11 or 15 lower alkyl esters thereof; provided, however, when said heteroaryl radical is a dichlorothienyl radical, the compound is not a 1-carboxylic add or amide thereof. Certain of the compounds represented by Formula I are novel and comprise another aspect of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

The present patent application is a continuation in part of U.S. patentapplication Ser. No. 861,414, filed on May 21, 1997 now U.S. Pat. No.5,798,378, which is a division of U.S. patent application Ser. No.740,883, filed Nov. 4, 1996, now U.S. Pat. No. 5,681,848, which is adivision of U.S. patent application Ser. No. 445,842, filed Jul. 11,1995, now U.S. Pat. No. 5,587,391, which is a division of U.S. patentapplication Ser. No. 174,535, filed Dec. 28, 1993, now U.S. Pat. No.5,545,665.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to cyclopentane heptanoic acid, 2heteroarylalkenyl derivatives which may be substituted in the 1-positionwith hydroxyl, alkyloxy, amino and amido groups, e.g. 1-OH cyclopentaneheptanoic acid, 2 heteroarylalkenyl derivatives. These compounds arepotent ocular hypotensive and are particularly suited for the managementof glaucoma.

2. Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure angle-closure glaucoma, theanterior chamber is shallow, the filtration angle is narrowed, and theiris may obstruct the trabecular meshwork at the entrance of the canalof Schlemm Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula: ##STR2##

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or α [[erg. prostaglandin F₂α(PGF₂α)].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins.Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF₂α, PGF₁α,PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkyl esters,e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF₂α has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as "the most potent ocular hypotensive agentever reported" [see, for example, Bito, L. Z., Arch. Ophthalmol. 105.1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF₂α and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The co-pending U.S. Ser. No. 596,430 (filed Oct. 10, 1990),relates to certain 1-acyl-prostaglandins, such as 11-pivaloyl, 1-acetyl,1-isobutyryl, 1-valeryl, and 11-isovaleryl PGF₂α. Intraocular pressurereducing 15-acyl prostaglandins are disclosed in the co-pendingapplication U.S. Ser. No. 175,476 (filed Dec. 29, 1993). Similarly,11,15-9,15 and 9,11-diesters of prostaglandins, for example11,15-dipivaloyl PGF₂α are known to have ocular hypotensive activity.See the co-pending patent applications U.S. Ser. No. Nos. 385,645 (filedJul. 7, 1989, now U.S. Pat. No. 4,994,274), 584,370 (filed Sep. 18,1990, now U.S. Pat. No. 5,028,624) and 585,284 (filed Sep. 18, 1990, nowU.S. Pat. No. 5,034,413). The disclosures of all of these patentapplications are hereby expressly incorporated by reference in theirentirety. This patent application is also related to U.S. patentapplication Ser. No. 08/726,921, which was filed on Oct. 7, 1996 in thename of Burk, which is a File Wrapper Continuation of U.S. patentapplication Ser. No. 08/443,992 which was filed on May 18, 1995 in thename of Burk, both of which patent applications are expresslyincorporated by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention concerns a method of treating ocular hypertensionwhich comprises administering to a mammal having ocular hypertension atherapeutically effective amount of a compound of formula I ##STR3##wherein the hatched segments represent a bonds, the solid trianglerepresents a β bond, the wavy segment represents α or β bond, dashedlines represent a double bond or a single bond, R is a substitutedheteroaryl radical having at least two pendant substituents selectedfrom the group consisting of lower alkyl, e.g. C1 to C₆ alkyl; halogen;trifluoromethyl; COR¹, COCF₃ ; SO₂ NR¹ ; NO₂ ; CN or at least one cyanosubstitutent, i.e. CN; R¹ is hydrogen or a lower alkyl radical having upto six carbon atoms, X is selected from the group consisting of --OR¹and --N(R¹)₂, Y is═O or represents 2 hydrogen radicals, and the 9, 11,or 15 lower alkyl esters thereof; provided, however, when saidheteroaryl radical is a dichloro thienyl radical, said compound is not a1-carboxylic acid or amide thereof. In a further aspect, the presentinvention relates to an ophthalmic solution comprising a therapeuticallyeffective amount of a compound of formula (I), wherein the symbols havethe above meanings, or a pharmaceutically acceptable salt thereof, inadmixture with a non-toxic, ophthalmically acceptable liquid vehicle,packaged in a container suitable for metered application. In particular,the substituents on the heteroaryl radical may be selected from thegroup consisting of lower alkyl, e.g. C₁ to C₆ alkyl; halogen, e.g.fluoro, chloro and bromo; trifluoromethyl (CF₃); COR¹, e.g. COCH₃ ;COCF₃ ; SO₂ NR¹, e.g. SO₂ NH₂ l NO₂ ; CN; etc.

In a still further aspect, the present invention relates to apharmaceutical product, comprising

a container adapted to dispense its contents in a metered form; and

an ophthalmic solution therein, as hereinabove defined.

Finally, certain of the compounds represented by the above formula,disclosed below and utilized in the method of the present invention arenovel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a schematic of the chemical synthesis of certain 1-carboxylicacid compounds of the invention specifically disclosed in Example5(a)-(e) below.

FIG. 2 is a schematic of the chemical synthesis of certain 1-carboxylicacid or 1-amido compounds of the invention specifically disclosed inExample 5(f) and 11(f), below.

FIG. 3 is a schematic of the chemical synthesis of certain 1-amidocompounds of the invention specifically disclosed in Examples 11(a)-(e),below.

FIG. 4 is a schematic of the chemical synthesis of certain 1-amidocompounds of the invention as specifically disclosed in Examples 11(g)-(j), below.

FIG. 5 is a schematic of the chemical synthesis of 1-isopropylestercompounds of the invention as specifically disclosed in Examples 12(a)-(b) and 12(k)-(l), below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of nonacidic cyclopentaneheptan(ene)oic acid, 2-heteroaryl alkenyl derivatives as therapeuticagents, e.g. as ocular hypotensives. The compounds used in accordancewith the present invention are encompassed by the following structuralformula I: ##STR4## wherein the substituents and symbols are ashereinabove defined. The dotted lines on bonds between carbons 5 and 6(C-5) and carbons 13 and 14 (C-13) indicate a single or double bond. Iftwo solid lines are used at C-5, or C-13, it indicates a specificconfiguration for that double bond. Hatched lines used at position C-8,C-9 and C-11 indicate the a configuration. A triangle at position C-12represents β orientation.

A preferred group of the compounds of the present invention includescompounds that have the following structural formula II: ##STR5##wherein Z is selected from the group consisting of O and S; A isselected from the group consisting of C or CR² ; R², R³ and R⁴ areselected from the group consisting of hydrogen, cyano, halogen and loweralkyl having from 1 to 6 carbon atoms. Preferably, when X is --N(R¹)₂, Yis ═O. More preferably, at least one of R², R³ or R⁴ are independentlyselected from the group consisting of chloro, bromo, iodo, cyano andmethyl.

In one aspect of the invention, at least one of R², R³ or R⁴ is 5 bromo,and at least one other of R², R³ or R⁴ is bromo or methyl, or R², R³ andR⁴ are chloro, or at least one other of R², R³ or R⁴ is methyl and atleast one other of R², R³ and R⁴ is bromo or iodo. In another aspect ofthis invention, R² is cyano and R³ and R⁴ are hydrogen.

Another preferred group includes compounds having the formula III:##STR6##

In the above formulae, the substituents and symbols are as hereinabovedefined and R⁵ is hydrogen.

The above compounds of the present invention may be prepared by methodsthat are known in the art or according to the working examples below.The compounds, below, are especially preferred representative of thecompounds of the present invention.

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5a)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5b)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5c)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-iodomethyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5d)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-((3-bromo-2,5-dimethyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5e)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)pentyl)-cyclopentyl]-5Z-heptenoicacid (5f)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11a)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11b)

7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5(-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11c)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11d)

7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-pentyl)cyclopentyl]-5Z-heptenamide(11f)

N-2-Hydroxyethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11g)

N-Ethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11h)

N-2-Hydroxyethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11i)

N-Ethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11j)

Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12a)

Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-chloro)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12b)

Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12k)

Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(121l)

A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Of particular interest are saltsformed with inorganic ions, such as sodium, potassium, calcium,magnesium and zinc.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace or in conjunction with it.

The ingredients are usually used in the following amounts:

    ______________________________________                                        Ingredient        Amount (% w/v)                                              ______________________________________                                        active ingredient about 0.001-5                                               preservative      0-0.10                                                      vehicle           0-40                                                        tonicity adjuster 1-10                                                        buffer            0.01-10                                                     pH adjuster       q.s. pH 4.5-7.5                                             antioxidant       as needed                                                   surfactant        as needed                                                   purified water    as needed to make 100%                                      ______________________________________                                    

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate the application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

The invention is further illustrated by the following non-limitingExamples, which are summarized in the reaction schemes of FIGS. 1through 5, wherein the compounds are identified by the same designatorin both the Examples and the Figures.

EXAMPLE 1 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5a) Step 1: Preparation of enone (2a)

To a suspension of sodium hydride (26 mg, 1.14 mmol) in tetrahydrofuran(THF) (2.1 mL) cooled to 0° C. was added dimethyl4-(5-(2-cyano)thienyl)-2-oxobutylphosphonate (325 mg, 1.14 mmol) in THF(2.1 mL). After 15 minutes a solution of aldehyde 1(500 mg, 1.03 mmol)in THF (3.0 mL) was added and the reaction solution was allowed toslowly warm to 23° C. over a period of 8 h. The reaction was quenchedwith saturated aqueous NH₄ Cl and extracted with ethylacetate (EtOAc).The combined organics were washed with brine, dried over MgSO₄, filteredand concentrated in vacuo. Purification by flash column chromatography(FCC) (silica gel, 3:1 hexane/EtOAc) provided 231 mg (37%) of enone 2a.

Step 2: Preparation of α-alcohol (3a)

Sodium tetrahydridoborate (15 mg, 0.40 mmol) was added to a solution ofenone 2a (231 mg, 0.38 mmol) in MEOH (3.0 mL) at 0° C. After 1 h thesolvent was removed in vacuo and the residue was stirred with 1N NaOHand EtOAc for 0.5 h. The resultant mixture was extracted twice withEtOAc. The combined organic portions were washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. Purification of the residueby flash column chromatography (silica gel, 2:1 hexane/EtOAc) afforded66 mg (29%) of pure α-alcohol 3a.

Step 3: Preparation of trihydroxy ester (4b/)

A solution of the α-alcohol 3b (66 mg, 0.11 mmol) and pyridiniump-toluenesulfonate (33 mg, 0.13 mmol) in MEOH (1.0 mL) was stirred at23° C. for 12 h. The solvent was removed in vacuo. The residue wasdiluted with EtOAc and then washed with 1N HCl, saturated aqueousNaHCO₃, and brine. The organic portion was dried over MgSO₄, filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 100% EtOAc) gave 28 mg (59%) of trihydroxyester 4b.

Step 4: Saponification of trihydroxy ester (4a)

Lithium hydroxide (0.3 mL of a 0.5 N solution in H₂ O, 0.15 mmol) wasadded to a solution of the trihydroxy ester 4a (28 mg, 0.081 mmol) inTHF (0.6 mL) at 23° C. After 16 h the reaction mixture was acidifiedwith 1N HCl and extracted with EtOAc. The organic portion was washedtwice with brine, dried over Na₂ SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography (silicagel, 9:1 CH₂ Cl₂ /MeOH) to afford 16 mg (60%) of the title compound 5a.

EXAMPLE 2 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl-5Z-heptenoicacid (5b)

In accordance with the procedures described above for the synthesis of5a, the use of dimethyl4-(5-(2,3,4-triiodo)thienyl)-2-oxobutylphosphonate afforded 38 mg offree acid 5b.

EXAMPLE 3 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5c)

In accordance with the procedures described above for the synthesis of5a, the use of dimethyl4-(5-(2,3-dichloro)thienyl)-2-oxobutylphosphonate afforded 10 mg of freeacid 5c.

EXAMPLE 4 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-(5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5d)

In accordance with the procedures described above for the synthesis of5a, the use of dimethyl4-(5-(2-iodo-4-methyl)thienyl)-2-oxobutylphosphonate afforded 22 mg offree acid 5d.

EXAMPLE 5 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(3-bromo-2,5-dimethyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid (5e)

In accordance with the procedures described above for the synthesis of5a, the use of dimethyl4-(4-(3-bromo-2,5-dimethyl)thienyl)-2-oxobutylphosphonate afforded 9 mgof free acid 5e.

EXAMPLE 6 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)pentyl)-cyclopentyl]-5Z-heptenoicacid (5f) Step 1: Preparation of enone (7)

To a suspension of sodium hydride (370 mg, 15.4 mmol) in tetrahydrofuran(THF) (12.0 mL) cooled to 0° C. was added dimethyl4-(3-(2,5-dichloro)thienyl)-2-oxobutyl-phosphonate (5.1 g, 15.4 mmol) inTHF (8.0 mL). After 15 minutes a solution of aldehyde 6 (3.55 g, 14.0mmol) in THF (5.0 mL) was added and the reaction solution was allowed toslowly warm to 23° C. over a period of 8 h. The reaction was quenchedwith saturated aqueous NH₄ Cl and extracted with EtOAc. The combinedorganics were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography(silica gel, 3:1 hexane/EtOAc) provided 4.4 g (69%) of enone 7.

Step 2: Preparation of THF ether (8)

Sodium tetrahydridoborate (194 mg, 5.14 mmol) was added to a stirredsolution of enone 7 (2.36 g, 5.14 mmol) in MEOH (10.3 mL) at 0° C. After2 h the solvent was removed in vacuo and the residue was diluted withsaturated aqueous ammonium chloride and EtOAc. The organic portion wasseparated, washed with brine, dried (MgSO₄), filtered and concentratedin vacuo to provide the corresponding allylic alcohol as a viscous oil.

A solution of the allylic alcohol and Wilkinson's catalyst (775 mg, 0.84mmol) in THF (7.0 mL) was evacuated and purged under an atmosphere ofhydrogen gas. After 12 h the solvent was removed in vacuo and theresidue was purified by FCC (silica gel, 3:1 hex/EtOAc) to furnish 824mg (29%) of the corresponding dihydro alcohol.

The dihydro alcohol (prepared above), 3,4-dihydro-2H-pyran (1.4 mL, 15.4mmol) and and pyridinium p-toluenesulfonate (39 mg, 0.15 mmol) in CH₂Cl₂ (3.1 mL) was stirred at 23° C. for 12 h. The reaction was dilutedwith EtOAc and washed with 1N HCl, saturated aq. NaHCO₃ and brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by FCC (silica gel, 3:1 hex EtOAc) to afford727 mg (75%) of THF protected ether 8.

Step 3: Addition of α-chain to 8:

Diisobutylaluminum hydride (0.86 mL of a 1.0 M solution in CH₂ Cl₂, 0.86mmol) was added to a solution of lactone 8 (313 mg, 0.57 mmol) in CH₂Cl₂ (1.2 mL) at -78° C. After 0.5 h the reaction was quenched withsaturated aqueous sodium potassium tartrate and allowed to warm to roomtemperature. The mixture was extracted with CH₂ Cl₂ and the organicportion was washed with brine, dried (Na₂ SO₄), filtered thenconcentrated in vacuo to provide the corresponding lactol as a clear,colorless oil.

To a suspension of (4-carboxybutyl)triphenylphosphonium bromide (800 mg,1.80 mmol) in THF (7.2 mL) was added potassium bis(trimethylsilyl)amide(718 mg, 3.6 mmol) at 0° C. After 0.5 h the reddish-orange mixture wascooled to -78° C. and a solution of the lactol (prepared above) in THF(3.0 mL) was added. The reaction mixture was allowed to warm to roomtemperature on its own accord. At this time it was quenched withsaturated aqueous NH₄ Cl and then extracted with EtOAc. The organicportion was washed with brine, dried (MgSO₄), filtered and concentratedin vacuo. FCC (silica gel, 3:2 EtOAc/hex) afforded 180.5 mg (50%) offree acid 10.

Step 4: Deprotection of bis-THF protected acid 10:

A solution of 10 (44 mg, 0.07 mmol) and pyridinium p-toluenesulfonate(21 mg, 0.084 mmol) in MEOH (1.0 mL) was stirred at 23° C. for 12 h. Thesolvent was removed in vacuo. The residue was diluted with EtOAc andthen washed with 1N HCl, saturated aqueous NaHCO₃, and brine. Theorganic portion was dried over MgSO₄, filtered and concentrated invacuo. Purification of the residue by flash column chromatography(silica gel, 100% EtOAc) gave 15 mg (46%) of trihydroxy acid 5f.

EXAMPLE 7 7-[3α,5α-Dihydroxy-2-(3(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11a)

Ammonia gas (˜4.5 mL) was condensed at -78° C. into a tube containingtrihydroxy ester 4a (52 mg, 0.12 mmol) and ammonium chloride (192 mg,3.56 mmol). The tube was then sealed and heated to 60° C. for 24 h. Atthis time the tube was cooled to -78° C., vented and allowed to warm toroom temperature on its own accord. The residue was dissolved insaturated aqueous NH₄ Cl and EtOAc. The organic portion was separated,dried over anhydrous MgSO₄, filtered and the filtrate was concentratedin vacuo. The residue was purified by flash column chromatography(silica gel, 9:1 CH₂ Cl₂ /MeOH) to provide 15 mg (30%) of the titlecompound 11a.

EXAMPLE 8 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11b)

In accordance with the procedures described above for the synthesis of11a, the use of trihydroxy ester 4b afforded 22 mg of amide 11b.

EXAMPLE 9 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11c)

In accordance with the procedures described above for the synthesis of11a, the use of trihydroxy ester 4c afforded 6 mg of amide

EXAMPLE 10 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5-heptenamide(11d)

In accordance with the procedures described above for the synthesis of11a, the use of trihydroxy ester 4d afforded 6 mg of amide 11d.

EXAMPLE 11 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-5-(3-(2,5-dichloro)thienyl)-pentyl)cyclopentyl]-5Z-heptenamide(11f)

A solution of free acid 10 (78 mg, 0.123 mmol), iodomethane (77 mL, 1.23mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL, 0.74 mmol) inacetone (1.0 mL) was stirred at 23° C. for 12 h. The reaction mixturewas concentrated in vacuo and the residue was purified by flash columnchromatography (silica gel, 3:1 EtOAc/hexane) to yield 53 mg of thecorresponding methyl ester.

A solution of the methyl ester (53 mg, 0.082 mmol) and pyridiniump-toluenesulfonate (25 mg, 0.098 mmol) in MeOH (0.5 mL) was stirred at23° C. for 12 h. The solvent was removed in vacuo. The residue wasdiluted with EtOAc and then washed with IN HCl, saturated aqueousNaHCO₃, and brine. The organic portion was dried over MgSO₄, filteredand concentrated in vacuo. Purification of the residue by flashchromatography (silica gel, 100% EtOAc) gave 28 mg of the correspondingtrthydroxy ester.

Ammonia gas (˜4.0 mL) was condensed at ˜78° C. into a tube containingthe trthydroxy ester (52 mg, 0.12 mmol) prepared above and ammoniumchloride (122 mg, 2.28 mmol). The tube was then sealed and heated to 60°C. for 72 h. At this time the tube was cooled to -78° C, vented andallowed to warm to room temperature on its own accord. The residue wasdissolved in saturated aqueous NH₄ Cl and EtOAc. The organic portion wasseparated, dried over anhydrous MgSO₄, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 9:1 CH₂ Cl₂ /MeOH) to provide 17 mg (52%) ofthe title compound 11f.

EXAMPLE 12 N-2-Hydroxyethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11g)

A solution of trihydroxy ester 4g (36 mg, 0.742 mmol) and2-hydroxyethylamine (0.43 mL, 7.2 mmol) in MeOH (4.0 mL) was heated to80° C. for 48 h. The reaction was cooled to room temperature andconcentrated in vacuo. The residue was purified by FCC (silica gel, 9:1CH₂ Cl₂ /MeOH) to afford 35 mg (92%) of amide 11g.

EXAMPLE 13

N-Ethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11h)

In accordance with the procedures described above for the synthesis of11g, the use of ethylamine afforded 25 mg (66%) of amide 11h.

EXAMPLE 14 N-2-Hydroxyethyl 7-3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11i)

In accordance with the procedures described above for the synthesis of11g, the use of trihydroxy ester 4i afforded 30 mg (58%) of amide 11i.

EXAMPLE 15 N-Ethyl 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide(11j)

In accordance with the procedures described above for the synthesis of11h, the use of trihydroxy ester 4j afforded 30 mg (61%) of amide 11j.

EXAMPLE 16 Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12a)

A solution of free acid 5a (38 mg, 0.090 mmol), 2-iodopropane (45 mL,0.45 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (40 mL, 0.27 mmol) inacetone (0.18 mL) was stirred at 23 ° C. for 12 h. The reaction mixturewas concentrated in vacuo and the residue was purified by flash columnchromatography (silica gel, 3:1 EtOAc/hexane) to yield 15 mg (36%) ofthe isopropyl ester 12a.

EXAMPLE 17 Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-(5-(2,3,4-trichloro)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12b)

In accordance with the procedures described above for the synthesis of12a, the use of free acid 5b afforded 12 mg (50%) of amide 12b.

EXAMPLE 18 Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5(3-bromo-2-methyl)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12k)

In accordance with the procedures described above for the synthesis of12a, the use of free acid 5k afforded 24 mg (56%) of amide 12k.

EXAMPLE 19 Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate(12l)

In accordance with the procedures described above for the synthesis of12a, the use of free acid 5l afforded 10 mg (14%) of amide 12l.

Certain of the above compounds were tested for activity in the variousin vitro assays described below and the results are reported in theTable.

Activity at different prostanoid receptors was measured in vitro inisolated smooth muscle preparations. FP-activity was measured ascontraction of the isolated feline iris sphincter. EP₁ -activity wasmeasured as contraction of the longitudinal smooth muscle of theisolated guinea pig ileum. EP₃ -activity was measured as inhibition ofthe twitch response induced by electrical field stimulation in theisolated guinea pig was deferens and as contraction of the longitudinalsmooth muscle of the isolated chick ileum. Activity was also measured asrelaxation of smooth muscle of isolated rabbit jugular vein apreparation which appears to contain a unique PGF₂α -sensitive receptorprovisionally termed FP_(VASC). TP-vasoconstrictor activity was measuredas contraction of rings of the isolated rat thoracic aorta. Effects onplatelets from healthy human donors were measured by incubatingplatelet-rich plasma with the compounds described herein. inhibition ofaggregation was determined by the ability of the compounds describedherein to inhibit platelet aggregation in platelet-rich plasma inducedby 20 μM ADP.

In addition to stimulating the FP receptor associated with the cat iris,several examples also stimulated the EP₃ receptor. Compounds withagonist activity at EP₃ receptors may also be used for treating gastricor duodenal ulcer by virtue of their cytoprotective and anti-secretoryproperties. They may also be used as adjunctive therapy in combinationwith aspirin-like drugs and steroids to limit gastrointestinal sideeffects. EP₃ agonists stimulate uterine smooth muscle and may be used toterminate pregnancy in human females. EP₃ agonists are also useful inthe cervical ripening process and could be used for inducing labor.

    __________________________________________________________________________                                                        Dog Monkey                                                                            Hyp/                                     EC.sub.50 (nM)                                                                          IC.sub.25                                                                          FP/EP.sub.4                                                                          Platelets                                                                            IOP IOP Mi-               AGN-#              FP  EP.sub.1                                                                         EP.sub.3                                                                         DP/EP.sub.2                                                                       EP.sub.4                                                                           Ratio                                                                             TP aggreg                                                                            inhib                                                                            (1 day)                                                                           (5                                                                                osis              __________________________________________________________________________     ##STR7##          28  NA        120  0.23                                                                              >10.sup.4                           194210                                                                        4ab                                                                            ##STR8##          1620          5438 0.3                                     194257                                                                        16f                                                                            ##STR9##          26            150600                                                                             0.0002                                  194262                                                                        8w                                                                             ##STR10##         3   >10.sup.4 64   0.05                                                                              7940                                194263                                                                        4ac                                                                            ##STR11##         214                                                        194329                                                                        8x                                                                             ##STR12##         40                                                         194330                                                                        16g                                                                            ##STR13##         24                                                         194338                                                                        4ad                                                                            ##STR14##         63                                                         194339                                                                        17                                                                            __________________________________________________________________________

    __________________________________________________________________________                                                        Dog Monkey                                                                            Hyp/                                     EC.sub.50 (nM)                                                                           IC.sub.25                                                                         FP/EP.sub.4                                                                          Platelets                                                                            IOP IOP Mi-               AGN-#              FP  EP.sub.1                                                                          EP.sub.3                                                                         DP/EP.sub.2                                                                       EP.sub.4                                                                          Ratio                                                                             TP aggreg                                                                            inhib                                                                            (1 day)                                                                           (5                                                                                osis              __________________________________________________________________________     ##STR15##         43                                                         5a                                                                             ##STR16##         12                                                         5b                                                                             ##STR17##         0.7                                                        5c                                                                             ##STR18##                                                                    5d                                                                             ##STR19##         3800           11775                                                                             03                                      5e                                                                             ##STR20##         20  >>10.sup.4         6920                                5f                                                                             ##STR21##         2950                                                       11a                                                                            ##STR22##                                                                    11b                                                                            ##STR23##         35                                                         11c                                                                           __________________________________________________________________________

    __________________________________________________________________________                                                        Dog Monkey                                                                            Hyp/                                    EC.sub.50 (nM)                                                                           IC.sub.25                                                                          FP/EP.sub.4                                                                          Platelets                                                                            IOP IOP Mi-               AGN-#              FP EP.sub.1                                                                          EP.sub.3                                                                         DP/EP.sub.2                                                                       EP.sub.4                                                                           Ratio                                                                             TP aggreg                                                                            inhib                                                                            (1 day)                                                                           (5                                                                                osis              __________________________________________________________________________     ##STR24##                                                                    11d                                                                            ##STR25##         8  NA                  NA                                  11f                                                                            ##STR26##         38 NA  NA                                                  11g                                                                            ##STR27##         25 >>10.sup.4 >135,135                                                                           <0.0002                                                                           NA                                  11h                                                                            ##STR28##         48 NA         185,185                                                                            0.0003                                                                            NA                                  11i                                                                            ##STR29##         32 NA         82360                                                                              0.0004                                                                            NA                                  11j                                                                            ##STR30##         115                                                        12a                                                                            ##STR31##         63                                                         12b                                                                            ##STR32##         10 NA  NA                                                  12k                                                                            ##STR33##         79                     NA                                  12l                                                                           __________________________________________________________________________

    __________________________________________________________________________                                                       Dog  Monkey                                                                            Hyp/                                   EC.sub.50 (nM)                                                                           IC.sub.25                                                                         FP/EP.sub.4                                                                          Platelets                                                                             IOP  IOP Mi-               AGN-#             FP EP.sub.1                                                                          EP.sub.3                                                                         DP/EP.sub.2                                                                       EP.sub.4                                                                          Ratio                                                                             TP aggreg                                                                            inhib                                                                             (1 day)                                                                            (5                                                                                osis              __________________________________________________________________________     ##STR34##        18 >>10.sup.4                                                                              57   0.3                                       194013                                                                        4x                                                                             ##STR35##        7.1          29685                                                                              0.0002                                                                            >10.sup.4                                                                        NA  NA                             194042                                                                        16a                                                                            ##STR36##        1.8                                                                              >10.sup.4 pa                                                                            335  0.005                                                                             2510       0.1%/  -5.5                194043                                                                        4y                                                                             ##STR37##        53           28090                                                                              0.002                                     194045                                                                        8r                                                                             ##STR38##        60           824  0.07                                      194047                                                                        16b                                                                            ##STR39##        8.6                                                                              NA        46200                                                                              0.0002                                                                            >10.sup.4                                                                        NA  >>10.sup.4                                                                        0.01%/  -3.4  0.1%/                                                           -3.0                       194054                                                                        8s                                                                             ##STR40##        5.6                                                                              >>10.sup.4                                                                              26393                                                                              0.0002                                                                            >10.sup.4                                                                        NA  NA  0.1%/  -4.2                194079                                                                        8t                                                                            __________________________________________________________________________

    __________________________________________________________________________                                                       Dog  Monkey                                                                            Hyp/                                   EC.sub.50 (nM)                                                                           IC.sub.25                                                                         FP/EP.sub.4                                                                          Platelets                                                                             IOP  IOP Mi-               AGN-#             FP EP.sub.1                                                                          EP.sub.3                                                                         DP/EP.sub.2                                                                       EP.sub.4                                                                          Ratio                                                                             TP aggreg                                                                            inhib                                                                             (1 day)                                                                            (5                                                                                osis              __________________________________________________________________________     ##STR41##        5.9                                                                              NA        133  0.04                                                                              NA                                    194080                                                                        16c                                                                            ##STR42##        0.9                                                                              NA        25   0.04                                                                              4570                                  194081                                                                        4z                                                                             ##STR43##        92           1070 0.09                                      194179                                                                        16d                                                                            ##STR44##        12 NA        186490                                                                             0.00006                                                                           NA NA  NA  0.01%/  -0.7  0.1%/                                                           -4.4                       194198                                                                        8u                                                                             ##STR45##        5.9          16   0.4                                       194199                                                                        4aa                                                                            ##STR46##        288          1130 0.25                                      194208                                                                        16c                                                                            ##STR47##        234          106655                                                                             0.02                                      194209                                                                        8v                                                                            __________________________________________________________________________

Other potential therapeutic applications are in osteoporosis,constipation, renal disorders, sexual dysfunction, baldness, diabetes,cancer and in disorder of immune regulation.

Many examples also have pronounced activity at the FP receptor,provisionally termed FP_(VASC) associated with the vascular endotheliumin the rabbit jugular vein preparation. Since such agents would bevasodilators they have potential in hypertension and any disease wheretissue blood perfusion is compromised. Such indications include, but arenot limited to, systemic hypertension, angina, stroke, retinal vasculardiseases, claudication, Raynauds disease, diabetes, and pulmonaryhypertension.

The compounds of the invention may also be useful in the treatment ofvarious pathophysiological diseases including acute myocardialinfarction, vascular thrombosis, hypertension, pulmonary hypertension,ischemic heart disease, congestive heart failure, and angina pectoris,in which case the compounds may be administered by any means that effectvasodilation and thereby relieve the symptoms of the disease. Forexample, administration may be by oral, transdermal, parenterial,subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal,or buccal routes.

The compounds of the invention may be used alone, or in combination withother of the known vasodilator drugs.

The compounds of the invention may be formulated into an ointmentcontaining about 0.10 to 10% of the active ingredient in a suitable baseof, for example, white petrolatum, mineral oil and petroatum and lanolinalcohol. Other suitable bases will be readily apparent to those skilledin the art.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional dissolving or suspending the compounds, which are alleither water soluble or suspendable. For administration in the treatmentof the other mentioned pathophysiological disorders. The pharmaceuticalpreparations which can be used orally include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer such as glycerol or sorbitol. The push-fit capsules cancontain the active compounds in liquid form that may be mixed withfillers such as lactose, binders such as starches, and/or lubricantssuch as talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as in buffered salt solution. In addition,stabilizers may be added.

In addition to being provided in a liquid form, for example in gelatincapsule or other suitable vehicle, the pharmaceutical preparations maycontain suitable excipients to facilitate the processing of the activecompounds into preparations that can be used pharmaceutically. Thus,pharmaceutical preparations for oral use can be obtained by adhering thesolution of the active compounds to a solid support, optionally grindingthe resulting mixture and processing the mixture of granules, afteradding suitable auxiliaries, if desired or necessary, to obtain tabletsor dragee cores.

Suitable excipients are, in particular, fillers such as sugars, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as inders such as starch, paste using forexample, maize starch, wheat starch, rich starchy, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, crosslinked polyvinyl pyrrolidone, agar,or algenic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which if desired, are resistant togastric juices. For this purpose, concentrated sugar solutions may beused, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Suitable formulations for intravenous or parenteral administrationinclude aqueous solutions of the active compounds. In addition,suspensions of the active compounds as oily injection suspensions may beadministered. Aqueous injectionsuspensions may contain substances whichincrease the viscosity of the suspension include, for example, sodiumcarboxymethyl cellulose, soribitol, and/or dextran. Optionally, thesuspension may also contain stabilizers.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

I claim:
 1. A method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of a cyclopentane heptan(ene)oic acid, 2-heteroaryl alkenyl compound represented by formula II ##STR48## wherein the hatched segments represent α bonds, the solid triangle represents a β bond, the wavy line represents either an α or β bond, R¹ is hydrogen or a lower alkyl radical hazing up to six carbon atoms, X is selected from the soup consisting of --OR¹ and --N(R¹)₂ ; Y is ═O or represents 2 hydrogen radicals, Z is selected from the group consisting of O and S, A is C when A is bonded directly to said alkenyl of said 2-heteroalkenyl of the compound and CR² when A is not bonded directly to said alkenyl of said 2-heteroalkenyI of the compound, R², R³ and R⁴ are selected from the group consisting of hydrogen, halogen, cyano and lower alkyl having from 1 to 6 carbon atoms and the 9,11, or 15 alkyl esters thereof.
 2. The method of claim 1 wherein said compound represented by formula III: ##STR49## wherein R⁵ is hydrogen.
 3. The method of claim 2 wherein X is --OH or --NH₂.
 4. The method of claim 2 wherein Y is ═O and X is --OH.
 5. The method of claim 2 wherein Y is ═O and X is --NH₂.
 6. The method of claim 2 wherein Z is S.
 7. The method of claim 6 wherein at least one of R², R³ and R⁴ are selected from the group consisting of cyano, chloro, bromo, iodo and methyl.
 8. The method of claim 6 wherein at least one of R², R³ and R⁴ is cyano.
 9. The method of claim 6 wherein at least two of R², R³ and R⁴ are chloro.
 10. The method of claim 6 wherein at least two of R², R³ and R⁴ are bromo.
 11. The method of claim 6 wherein at least two of R², R³ and R⁴ are methyl.
 12. The method of claim 6 wherein at least one of R², R³ and R⁴ is methyl and at least one of R², R³ and R⁴ are chloro.
 13. The method of claim 11 wherein at least one of R², R³ or R⁴ are bromo and at least one of R², R³ or R⁴ are methyl.
 14. The method of claim 13 wherein said compound is selected from the group consisting of7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5a) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-5-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5b) b 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5c) 7-[3α, 5-Dihydroxy-2-(3α-hydroxy-5(-5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5d) b 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-bromo-2,5-dimethyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5e) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)pentyl)-cyclopentyl]-5Z-heptenoic acid (5f) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11a) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11b) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11c) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamnide (11d) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-pentyl)cyclopentyl]-5Z-heptenamide (11f) N-2-Hydroxyethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11g) N-Ethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11h) N-2-Hydroxyethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11i) N-Ethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11j) Isopropyl 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12a) Isopropyl 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-trichloro)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12b) Isopropyl 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12k) and Isopropyl 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12l).
 15. The cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl compound represented by Formula III: ##STR50## wherein the hatched segments represent α bonds, the solid triangle represents a β bond; the dashed bond represents a double bond or a single bond; R⁵ represents hydrogen or a lower alkyl radical having up to six carbon atoms; X is selected from the group consisting of --OR¹ and --N(R¹)₂ ; Y is ═O or represents 2 hydrogen radicals; R¹ is hydrogen or a lower alkyl radical having up to six carbon atoms; Z is selected from the group consisting of O and S, A is C when A is bonded directly to said alkenyl of said 2-heteroalkenyl of the and CR² when A is not bonded directly to said alkenyl of said 2-hetero alkenyl of the compound; R², R³ and R⁴ are selected from the group consisting of hydrogen, halogen, cyano and lower alkyl having from 1 to 6 carbon atoms; wherein at least two of the radicals represented by R², R³ and R⁴ are halogen, cyano, or a lower alkyl radical having from 1 to 6 carbon atoms; and the 9,11, or 15 alkyl esters thereof.
 16. The cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl compound represented by Formula III: ##STR51## wherein the hatched segments represent α bonds, the solid triangle represents a β bond; the dashed bond represents a double bond or a single bond; R⁵ represents hydrogen or a lower alkyl radical having up to six carbon atoms, X is selected from the group consisting of --OR¹ and --N(R¹)₂ ; Y is ═O or represents 2 hydrogen radicals; R¹ is hydrogen or a lower alkyl radical having up to six carbon atoms; Z is S, A is C when A is bonded directly to said alkenyl of said 2-heteroalkenyl of the and CR² when A is not bonded directly to said alkenyl of said 2-hetero alkenyl of the compound; R², R³ and R⁴ are selected from the group consisting of hydrogen, halogen, cyano and lower allyl having from 1 to 6 carbon atoms; wherein at least two of the radicals represented by R², R³ and R⁴ are halogen, cyano, or a lower 1 radical having from 1 to 6 carbon atoms; and the 9, 11, or 15 alkyl esters thereof.
 17. The compound of claim 16 wherein at least one of R², R³ and R⁴, are selected from the group consisting of cyano, chloro, bromo, iodo and methyl.
 18. The compound of claim 17 wherein at least one of R², R³ and R⁴ is cyano.
 19. The compound of claim 17 wherein at least two of R², R³ and R⁴ are chloro.
 20. The compound of claim 17 wherein at least two of R², R³ and R⁴ are bromo.
 21. The compound of claim 17 wherein at least two of R², R³ and R⁴ are methyl.
 22. The compound of claim 17 wherein at least one of R²,R³ and R⁴ is methyl and at least one of R², R³ and R⁴ are chloro.
 23. The compound of claim 17 wherein at least one of R², R³ or R⁴ are bromo and at least one of R², R³ or R⁴ are methyl.
 24. The compound of claim 17 wherein said compound is selected from the group consisting of7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5a) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5b) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5c) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5d) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(4-(3-bromo-2,5-dimethyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid (5e) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)pentyl)-cyclopentyl]-5Z-heptenoic acid (5f) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11a) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3,4-trichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11b) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11c) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-iodo-4-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11d) 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-pentyl)cyclopentyl]-5Z-heptenamide (11f) N-2-Hydroxyethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide (11g) N-Ethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo-2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamnide (11h) N-2-Hydroxyethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamnide (11i) N-2-Hydroxyethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamnide (11i) N-Ethyl 7-[3α, 5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamnide (11j) Isopropyl 7-[3α, 5α- Dihydroxy-(2-(3α-hydroxy-5-(2-cyano)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12a) Isopropyl 7-[3α, 5α- Dihydroxy-(2-(3α-hydroxy-5-(5-(2,3,4-thienyl)-1E-pentenyl)cyclopentyl]-5Z- heptenoate (12b) Isopropyl 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(5-(3-bromo)2-methyl)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12k)Isopropyl 7-[3α, 5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate (12l). 